A Look Back at 2010 HIV/AIDS Research, a Clinical Context Report

In this exclusive video report, Michael Smith reviews some of the most important news out of the 2010 ICAAC and IDSA Meetings with a leading expert in the field. Here's a transcript of their discussion.

MICHAEL SMITH: This is Michael Smith with MedPage Today. I'm here with Dr. Barry Zingman. He's medical director of the AIDS Center and Clinical Director of Infectious Diseases at Montefiore Medical Center in New York City, and he's also a professor of clinical medicine at Albert Einstein College of Medicine. Dr. Zingman, welcome back to MedPage Today.

DR. BARRY ZINGMAN: Thank you, Michael.

MICHAEL SMITH: Good to see you. A lot has gone on at the end of the year, at the two major meetings in which HIV plays a prominent role. Of course, ICAAC (The Interscience Conference on Antimicrobial Agents and Chemotherapy) and the Infectious Diseases Society of America. Let's begin with what's been dubbed the "quad pill." Tell me about that.

DR. BARRY ZINGMAN: The quad pill is an unofficial name given to the combination pill that has a new integrase inhibitor elvitegravir, with a new booster, cobicistat, as well as tenofovir and emtricitabine. The quad pill is being studied now especially for initial therapy, and the study that you're referring to compared it to Atripla in a phase II study, a small phase II study.

MICHAEL SMITH: Okay, and actually, this is a fairly complicated piece of research because they were actually on the one hand comparing the two main drugs, and then they were also comparing a different drug, but boosted with either ritonavir, the standard booster, or this new one, cobicistat.

DR. BARRY ZINGMAN: Right, in the study that was demonstrated at ICAAC, they combined the results of the two studies so that they were able to look at overall efficacy, side effects, and mutations with the quad drug, irrespective of which study it was in. And so, yes, in one study, the results were combined, but there was cobicistat used as a booster, and Norvir as a booster in comparison.

MICHAEL SMITH: Now, I guess a single pill is always a good thing. Why would anybody want to necessarily change the booster?

DR. BARRY ZINGMAN: There are a couple of reasons why the quad pill would be of interest to people with HIV and to providers. It's because there are two differences between the quad pill and Atripla. One is the substitution of efavirenz, putting in evitegravir, an integrase inhibitor. The second is that cobicistat may be used instead of ritonavir as a booster in other situations. Efavirenz in Atripla has significant rates of neurological side effects. About 10% of people can't tolerate it. In the studies so far, including the study presented at ICAAC, there were significantly less adverse events in the quad drug arm. And very significantly fewer neurologic events that required discontinuation.

In other studies and other combinations in which you might be considering a booster, and that would include boosting other protease inhibitors, Norvir (ritonavir) has always been a problem. We've been seeking a substitute for it. Ritonavir has significant metabolic abnormalities associated with it. It's a very, very strong booster and it has many drug interactions. It causes very significant hyperlipidemia, especially hypertriglyceridemia. And so cobicistat may be able to boost other drugs in the regimen especially without those metabolic side effects.

MICHAEL SMITH: Now, you pointed out that this is a small study and it's a phase II study. Presumably, they now have to take this quad pill and move it into more advanced trials?

MICHAEL SMITH: Let's talk about another new one. This is a drug, TMC278, or rilpivirine. This, again, this is an early stage trial, but the investigators at ICAAC said that the drug was a trade-off. Tell me about that. Why is it a trade-off?

DR. BARRY ZINGMAN: Yes, so in the same way as the quad pill is being compared with Atripla as a potential replacement, rilpivirine is being combined with tenofovir/emtricitabine, and compared to Atripla. That's because, again, Atripla has significant neurologic side effects due to the efavirenz, where rilpivirine may not.

The results that were demonstrated at the meeting showed that overall there was noninferiority in viral suppression between the two arms, the rilpivirine combination or Atripla, no significant differences. There was a small difference that wasn't statistically significant, about a 5% difference in viral suppression between the two arms, but not statistically significant. However, the biggest difference was found if you broke down patients into their viral load strata. If they entered the study with viral load over 100,000, the Atripla patients did significantly better. The viral suppression rates were about 83%, whereas with rilpivirine the viral suppression rates were about 73%.

In fact, in patients with under 100,000 viral load starting the study, the rilpivirine patients did better. And in both arms, there were fewer stoppages for side effects with rilpivirine. So, the mixed results would be good on side effects, but maybe some patients, especially those with high viral loads, may not do as well on it.

MICHAEL SMITH:Here's a drug that's been around for a while. Darunavir (Prezista), and at ICAAC, we had data that showed that the drug can be given once a day to treatment experienced patients without the danger of resistance. We didn't see any resistance at all when they gave, I think it was 800 mg versus 600 twice a day, and in both cases, boosted with ritonavir at 100 mg. What does this mean? And I should say that the drug has now been approved in that dosage and for those patients. What does this do?

DR. BARRY ZINGMAN: This is a significant advance for patients who require protease inhibitor treatment, a major advance. Darunavir has been certainly one of the top two to three preferred protease inhibitors. It's well tolerated and it has a lower rate of development to resistance. And so it was formally approved for once a day dosing, with Norvir, only for treatment naive patients. There had not been approval yet for people past their first regimen. Even though they may never have been on a protease inhibitor before, there just wasn't the data.

Now we have the data. The ODIN study showed that patients who even had antiretroviral experience, although they didn't have resistance mutations to darunavir, were very effectively treated with the standard once daily dosing of darunavir, 800 mg with 100 mg ritonavir. And the benefit to that is multiple. The simplicity of the regimen is much better and the tolerability is much better, as we're using less darunavir. We're using half as much ritonavir, so there would be significantly fewer metabolic side effects, like hyperlypidemia. So, it won easy approval, because it was a very effective treatment.

MICHAEL SMITH: And that's good then.

DR. BARRY ZINGMAN: Very exciting.

MICHAEL SMITH: Very exciting for those of you who are prescribing to patients, and presumably the patients themselves will welcome this.

DR. BARRY ZINGMAN: Yes.

MICHAEL SMITH: Let's finish ICAAC with, I guess, a bit of a downer, a drug that we had high hopes for although it ran into some earlier difficulty. Vicriviroc, the CCR5 inhibitor -- at ICAAC, the developer, Merck, decided to announce that, basically, they weren't happy with its progress and they were going to pull the plug on it. Why is that?

DR. BARRY ZINGMAN: Vicriviroc was shown in treatment-experienced patients, heavily treatment-experienced patients, that the virologic suppression of the two arms was similar, a little bit lower in vicriviroc arm, but the company decided that there was not enough reason to move forward with the drug. It didn't provide significant advantages, and the CCR5 inhibitor class has had difficulties catching on. Maraviroc is currently approved but not widely used, and so I think that their assessment that it wasn't clearly much better than what's out there right now, plus with the limited market, they decided to not move forward with it.

MICHAEL SMITH: Well, and that, I think, wraps up ICAAC. Let's turn to the later meeting in Vancouver. The Infectious Diseases Society of America. And I think that now we're moving from medications into how to use them. Let's begin with the issue of testing. And this has been a controversial issue, but certainly the CDC recommended a broader testing regimen across the board a couple years back. And yet we found a report here that even in the largest sort of institutional population, the Veterans Affairs, they were not testing their vets as much as you might think. What's the issue here?

DR. BARRY ZINGMAN: Let's go back to two things. One is that in 2006, the CDC recommended expanded routine testing for HIV in people up to ages 64, and, secondly, the Veterans' Administration was even able to get rid of written informed consent. Despite this, a year later, they did a national survey of veterans receiving care in VA health centers. They demonstrated in the study that HIV testing was very low. It ranged from as low as 3 to 5% in some cities up to 15 to 20% in some of the higher prevalence cities. But even in those higher prevalence cities, like Washington, D.C., or New York City, testing was very low, relative to really what it should be. And in the VA health system they had very few barriers to doing testing.

So it speaks to a problem with many things. It speaks to how difficult it is for providers to remember to offer HIV tests. It no doubt speaks to patients refusing HIV testing. It probably also speaks to doctors being very busy with many, many requirements. And they have not clearly begun to put it into their care. Like, asking about seat belts, maybe, has become part of routine questioning HIV testing has not become that routine.

MICHAEL SMITH: And whereas most doctors will be aware of things. They'll do blood work for lipids.

DR. BARRY ZINGMAN: That's right.

MICHAEL SMITH: They'll do blood work for a whole bunch of things. This is not top of mind in many cases.

DR. BARRY ZINGMAN: That's right. They'll even do blood testing for syphilis every single year, even in very, very low risk populations, but won't do an HIV test, which, actually, is much more likely in many, many parts of the country.

MICHAEL SMITH: On the other hand, another paper here showed that it's possible to target some high-risk populations, quite effectively. And this is of the populations of people going through the jails now. As opposed to prisons. If you're in prison, you're there for a long time. People go to jail for two months, three months. Sometimes only days. But this is still a high-risk population. This paper showed that, in fact, you can use the rapid tests to capture some of those people and perhaps get them tested and treated.

DR. BARRY ZINGMAN: That's right. I believe it was in jails in Rhode Island, Philadelphia, and Baltimore. They were able to develop very successful rapid HIV testing programs. I believe it was built around OraQuick rapid HIV testing of people entering jails. This is the first time that this has been tried on such a large scale and it was very successful. Thousands of people were tested and hundreds of people were newly diagnosed with HIV. And in the study, in fact, 15% of all new diagnoses of HIV in Rhode Island were made through this program during that time period. That's an amazing percentage. And before that, no testing would have been done at their jails. They would have missed 15% of all their new positives in the state if they had not done this. It's really remarkable.

MICHAEL SMITH: Okay, on the positive side, I mean, that's obviously a good thing because now those people know their HIV status, they can get treatment, which has a number of positives, as we know. We did find, there was a paper again, at IDSA, suggesting that we are still not seeing physicians -- and the way the writer at the time phrased it -- "jumping on the bandwagon of earlier treatment." Why are docs not -- and I use the phrase again -- "jumping on the bandwagon?"

DR. BARRY ZINGMAN: This was a retrospective study of experienced HIV care sites in a number of cities around the country. What they found was that significant numbers of people who met criteria for antiretroviral use -- had CD4 counts under 350 or, using a later guideline, CD4 under 500 -- were not on antiretroviral therapy, and they proposed that this may be that physicians are not jumping on the bandwagon, not agreeing with the guidelines. That may be true. But I actually wonder if it's much more than that. I think what it probably better demonstrates is that there were many barriers to getting people on treatment.

One barrier is knowledgeable providers. I doubt that lack of knowledge or understanding or agreement with the guidelines was present at these experienced sites. But I do know what would have been found at these sites would be certainly insurance difficulties, active substance use, mental illness that may prevent continuity of care. Certainly, there may have been poor follow-up of some patients, leading their providers to not feel comfortable prescribing the medications for them yet. Patients may not have been interested in therapy, there may have been insurance issues. ADAP waiting lists exist around the country.

So, I don't argue with the data. I'm sure, and I know in my own clinic, people who should be on therapy are not. But I think the reason why is complicated and multifactorial. And I think what it most argues for is the need to provide full supportive services for people with HIV.

MICHAEL SMITH: That said, you did point out, that experienced providers, and there was a study, again, at IDSA that suggested that experienced providers, such as yourself and, of course, many others around the country, actually are able to boost adherence to treatment. And presumably, that's because of some of the things you just mentioned, that they are aware of those issues. But, what the study found is something like if a provider had more than 100 patients, any given patient had a 44% increase in the chance of having a low viral load.

DR. BARRY ZINGMAN: That's right.

MICHAEL SMITH: After 24 months of treatment. This is good news.

DR. BARRY ZINGMAN: That's right. This was a Kaiser Permanente study that was retrospective using a very large provider and patient database, and I'm really happy and not surprised to see that experienced providers made a difference. It's not surprising to me that choices of therapy might be better when made by experienced providers, that better preparation of patients might be made, more experienced providers might be able to bring people through side effects more effectively. They may have better support systems in place. They may be able to have better use of resources to help their patients, so it's not surprising to me that experienced providers would have better outcomes. However, the study also did show that some of the more recent regimens seemed to ameliorate this effect. So, some of the non-nucleoside-based regimens like Atripla seemed to lower the effect of an experienced provider. And I think we see that as well, that less experienced providers are able to easily remember Atripla and prescribe it.

It's three medicines in one. The advantages of medications like the quad pill, multiple medicines in one, and also of a well-tolerated pill, are clear, and we're looking for better tolerated pills. These kinds of combination pills, newer combination pills, will expand the benefits of treatment to more people. And so providers with less experience should be able to give them and with good outcomes. Whether or not it will ever match what very experienced providers do, I don't know. But it certainly makes sense to think that very simple, well-tolerated regimens, easily prescribed, should be able to be prescribed by inexperienced people or experienced people. And that's a wonderful thing that we're seeing an evolution in HIV care, to well-tolerated combination pills.

MICHAEL SMITH: So, two very interesting meetings. A lot of stuff. And we've, of course, just skimmed over the top, but thank you for your time, Dr. Zingman. I'm Michael Smith. MedPage Today.

Barry Zingman, MD, has disclosed that he has no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.